The objective of our research is to gain insight into how protein kinase C (PKC) regulates G-protein coupled phospholipase CB-mediated signal transduction. This signaling mechanism is widely employed in the central nervous system for the action of several neurotransmitters including glutamate, serotonin, acetylcholine, norepinephrine, and histamine. Activation of phospholipase CB-3 leads to generation of two messengers: diacylglycerol (DAG) and inositol trisphosphate (1P3). IP3 mobilizes intracellular calcium whereas DAG activates PKC. PKC has been implicated in regulation of signal transduction as well as diverse cellular processes including growth, differentiation, and tumorigenesis. We will use the visual transduction in Drosophila melanogaster as a model system. In the visual cascade, E photoreceptor-specific protein kinase C (eye-PKC) is involved in desensitization, deactivation and light adaptation of the visual signaling. We previously showed that eye-PKC is tethered to a signal transduction complex by interacting with an adaptor protein INAD. A lack of the INAD-eyePKC interaction leads to a loss of in vivo activity of eye-PKC. Moreover, we demonstrated that INAD and TRP, which also associate with INAD, are phosphorylated by eye-PKC. We will: (1) identify eye-PKC phosphorylation sites in INAD; (2) investigate how phosphorylation of INAD affects protein-protein interactions with other components of the signaling complex; (3) identify eye-PKC phosphorylation sites in TAP; (4) investigate how phosphorylation of TRP may modulate the channel activities and protein-protein interaction with INAD; and (5) investigate if NORPA is also a substrate of eye-PKC and how NORPA is regulated by phosphorylation. PKC regulates many facets of cellular function. We believe that our research on regulation of G-protein coupled signaling by PKC will provide insight into modulation of cell-cell communications in the nervous system. Un-regulated signaling may lead to hyperactivity or degeneration of neurons, which has been implicated in mans pathophysiological conditions such as epilepsy and neurodegenerative diseases.
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